Genomic instability is a hallmark of cancer, yet is underdeveloped as a therapeutic target area The central goal of this program is to develop new cancer therapeutics that target genomic instability as a hallmark of cancer cells, bringing new, cancer-cell selective treatments to the clinical oncology market. Two key challenges in current cancer therapy are minimizing the side effects associated with chemotherapy;and preventing tumor cell "evolution" by acquired mutations that drive cancer progression and therapy resistance. Therapies that target genomic instability mechanisms have the potential to meet these critical clinical challenges. In recent years, the B-cell specific DNA mutase/recombinase Activation Induced Cytidine Deaminase (AID) has been implicated as a driver of oncogenic genomic instability. While its expression is normally restricted to activated, germinal center B-cells, AID is also overexpressed in a range of human neoplasms, especially B-cell lymphomas and leukemias. Cyteir Therapeutics, Inc. has partnered with The Jackson Laboratory to develop new cancer therapeutics that target AID-induced genomic instability to induce tumor-cell self-destruction with few off target side effects. This approach takes advantage of the discoveries that: (1) AID creates widespread DNA double strand breaks (DSBs) throughout the genome;and (2) the RAD51 family of DSB repair factors is critical for leukemic cells to survive this damage. In vitro, reduction in RAD51 function causes AID-mediated tumor cell death, but is tolerated by cells lacking AID expression, such as most normal tissues.
The aims of this feasibility study are to assess the in vivo efficacy of targeting RAD51 using leukemia and lymphoma xenograft models;and to generate derivatives of our early RAD51 inhibitor lead that have drug-like pharmacokinetic properties, while retaining potency and specificity for AID-expressing tumors. We are focusing our current preclinical development efforts on B-cell neoplasms, such as non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL) that often requires intensive, long-term chemotherapy. There is still an unmet clinical need in these cancers, because conventional therapies can be physically taxing, cause severe and sometimes life-threatening side effects, and often fail to achieve cure. These Phase I feasibility studies will accelerate the preclinical development of new therapeutics that target genomic instability mechanisms, and will pave the path for their clinical and commercial development. !

Public Health Relevance

There are roughly 137,000 new cases of lymphoma, leukemia and multiple myeloma in the United States annually, and in excess of 54,000 deaths. Although therapies have improved somewhat, these cancers are still increasing in incidence worldwide. Owing to the rigors of chemotherapy, there are significant long-term health concerns relating to survivorship. The conventional first-line therapies for lymphoid cancers can produce difficult and sometimes life-threatening side effects, but are often non-curative. Thus, there is a significant, unmet need for new therapeutics that effectively treats the cancer but elicit fewer side effects. Our novel therapeutic strategy promises to selectively target lymphoid cancer cells for self-destruction, while minimizing the side effects associated with conventional chemotherapies. Given the continued increase in global lymphoma and leukemia incidence, and the insufficiency of current therapies, there is a significant clinical and commercial market for effective and selective therapeutics, both domestically and worldwide. In this context, we have potential to positively impact a substantial cancer patient population, and to improve the quality of life of many who require chemotherapy treatment.